Heroin, cocaine, and alcohol addictions, alone and in combination, along with their frequent medical complications, including hepatitis B and C, AIDS, and psychiatric comorbidity, remain the major medical problems confronting our nation and much of the world. Effective treatments must be based on a fundamental understanding of the biological basis of each specific addictive disease, including the effects of exposure to drugs of abuse. Our NIH-NIDA Treatment Research Center will continue to identify and study the molecular, neurobiological, genetic and other biological correlates of the addictions, with focus on the role of the endogenous opioid system, and also factors which might affect treatment outcome. In this proposal for the continuation of our ongoing Center, all laboratory and clinical research studies have been developed on an interactive basis, relying upon the Center for their integration. Bidirectional translational research is the hallmark of the work of the Center. Research findings and observations from basic and applied clinical research are used to formulate specific hypotheses to be tested in laboratory research. Conversely, findings from laboratory research will be applied as promptly as feasible and appropriate, into clinical research, and then to the clinic. The specific projects proposed include: 1) effects of chronic opiates and cocaine, withdrawal, and challenge, on ultrastructure, receptors and gene expression of the endogenous opioid and related neurotransmitter systems; 2) effects of opiates and cocaine on the molecular biology and expression of the stress responsive hypothalamic-pituitary-adrenal axis; 3) biotransformation and pharmacodynamics of opioid and related neuropeptides: modulation of dopaminergic function and cocaine effects; 4) neuroendocrine effects of opiates and cocaine: role of the endogenous opioids and stress responsivity in addictive diseases; and 5) a conditional knockout of glutamatergic receptors involved in opioid and cocaine abuse. Scientific projects will be integrated through the eight Research Core resources, including a Research Training core, strengthening interactions to foster the synergism which only a Center can provide. We propose changing our P50 Specialized Center to a P60 Comprehensive Center because of increased training and information dissemination activities.